The HLA class I antigen is formed by a heterodimer of a 45-KD α chain comprising three domains (α1, α2, α3), and a 12-KD β2 microglobulin. The main role of the HLA molecule is to present CD8+T cells with antigenic peptides, formed from about eight to ten amino acids produced inside cells. As such, it plays a very important role in the immune response and immune tolerance induced by this peptide presentation.
By ligating HLA class IA antigens with antibodies, cell growth-suppressing and cell death-inducing effects have been observed in lymphocytes, suggesting that HLA molecules may also be signal transduction molecules.
More specifically, for example, there are reports showing cell growth suppression of activated lymphocytes by the B9.12.1 antibody against the α1 domain of human HLA class IA, the W6/32 antibody against the α2 domain, and the TP25.99 and A1.4 antibodies against the α3 domain (non-patent literature 1, 2). Furthermore, two types of antibodies, MoAb90 and YTH862, against the α1 domain have been reported to induce apoptosis in activated lymphocytes (non-patent literature 2, 3, 4). Apoptosis induced by these two antibodies has been shown to be a caspase-mediated reaction (non-patent literature 4), and therefore, HLA class IA antigens expressed in lymphocytes are also speculated to be involved in apoptosis signal transduction.
Furthermore, the 5H7 antibody against the α3 domain of human HLA class IA (non-patent literature 5), and the RE2 antibody against the α2 domain of mouse HLA class IA (non-patent literature 6) have been also reported to induce cell death in activated lymphocytes and the like. However, in contrast with the aforementioned apoptosis-inducing antibodies MoAb90 and YTH862, none of the cell deaths induced by these antibodies have been shown to be mediated by caspase. Accordingly, cell deaths due to 5H7 and RE2 are predicted to be of a type completely different from conventionally known apoptosis mechanisms.
As described above, there are numerous reports of the cell growth-suppressing actions and cell death-inducing actions of anti-HLA antibodies. However, the antibodies used herein are all in the molecular forms of IgG antibodies, F(ab′)2, or Fab. To date there have been no reports that cell death-inducing activity is enhanced by reducing the molecular weight of antibodies, as in F(ab′)2 and Fab.
The 2D7 antibody is a mouse monoclonal antibody obtained by immunizing Balb/c mice with human myeloma cells (non-patent literature 7). The 2D7 antibody has been observed to bind very specifically to the cell surface of various lymphoid tumor cells, however, antigens recognized by the 2D7 antibody have not been identified.
Prior art literature relating to the present invention of this application is shown below.    [Non-patent Document 1] Fayen et al., Int. Immunol. 10: 1347-1358(1998)    [Non-patent Document 2] Genestier et al., Blood 90: 3629-3639 (1997)    [Non-patent Document 3] Genestier et al., Blood 90: 726-735 (1997)    [Non-patent Document 4] Genestier et al., J. Biol. Chem. 273: 5060-5066 (1998)    [Non-patent Document 5] Woodle et al., J. Immunol. 158: 2156-2164 (1997)    [Non-patent Document 6] Matsuoka et al., J. Exp. Med. 181: 2007-2015 (1995)    [Non-patent Document 7] Goto, et al. Blood 84: 1922 (1994)